4H-[1,3,5,2]oxadiazaphospholo[3,4-a][1,5]benzodiazepin-1-amine-1-oxides: synthesis and computational studies

The modification of heterocyclic systems still remains one of the most promising areas in heterocyclic chemistry. Benzodiazepines (BZDs), representing a diverse class of heterocyclic molecules, have piqued the interest due to their use as anticonvulsant/anti-inflammatory/analgesic/sedative/anti-depressive/hypnotic medications, as well as anti-inflammatory/anti-HIV drugs. Particular attention was focused on the phosphorus heterocycle molecules fused with the rings of different sizes and bearing various hetero-atoms. Phosphoramidate class compounds with an amino group linked directly to the phosphorus atom have gained considerable attention due to their broad range of biological activity and agricultural application. To date, however, only non-condensed monocyclic 1,3,5,2-oxodiazaphosphol-2-oxides have been described.

Herein we report the synthesis of previously undescribed 4H-[1,3,5,2]oxadiazophospho[3,4-a][1,5]benzodiazepine-1-amino-1-oxides, comprising benzodiazepine and a fused five-member oxodiazophospholo cycle with four heteroatoms in the "a" position, which has made possible by phosphorylation of 1,3,4,5-tetrahydro-2H-1,5-benzodiazepin oximes with an equimolar amount of dimethylaminophosphoric acid dichloride. The chemical structures of the compounds were confirmed by IR, ¹H, ¹³C and ³¹P NMR spectral analysis. A series of simulations were run using the semi-empirical tight-binding computational approach GFN2-xTB to reveal the likely pathways leading to their formation.

The synthesized compounds obeyed Lipinski's rule, implying a high bioavailability, and assessment of their projected drug-like abilities revealed that they may have a strong anti-neoplastic potency and may serve as both substrates and inducers of cytochrome P-450 (CYP) super-family enzymes.